JP4794794B2 - Treatment of brain, spinal cord and nerve damage - Google Patents
Treatment of brain, spinal cord and nerve damage Download PDFInfo
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- JP4794794B2 JP4794794B2 JP2001552892A JP2001552892A JP4794794B2 JP 4794794 B2 JP4794794 B2 JP 4794794B2 JP 2001552892 A JP2001552892 A JP 2001552892A JP 2001552892 A JP2001552892 A JP 2001552892A JP 4794794 B2 JP4794794 B2 JP 4794794B2
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
Description
【０００１】
（発明の分野）
本発明は、脳、脊髄および神経損傷の処置の方法に関する。該方法に特に役立つ処方物も提供される。
【０００２】
脳に対する損傷は、運動および認識の欠損の発生を招き、それは、脳損傷の生存者が経験する有意な病的状態に寄与する。その上、社会の若い成員に最高の発生率を有する。したがって、脳に対する損傷は、他のいかなる疾病過程に比較しても、生産生活の最大の損失の原因となる。にもかかわらず、脳損傷後の結果を改善するのに効果的な治療法は、皆無である。本発明者らは、脳損傷の治療のための力強い薬理学的介入としての治療法の用途を開示する。この治療法を用いることは、軽度ないし重度の実験的脳損傷における運動と認識との双方の結果を有意に改善し、また脊髄および神経損傷の治療にも有益な効果を有することが見出された。
【０００３】
（発明の背景）
脳損傷は、二つの機序を通じて神経学的欠損の発生を招くことが周知である。これらの第一は、一次機序として知られている。これらは、損傷の事象の時点で発生し、神経繊維の断裂、裂傷、伸張および圧縮のような、機械的過程を包含する。一旦発生したときのこの種の損傷に対しては、僅かなことがなし得るにすぎない。第二の機序は、二次損傷であって、一次損傷によって開始される、生化学的および生理学的過程を包含するが、損傷後の時間とともに現れる。脳損傷後の罹患率の多くは、この二次損傷の発生に関連することが立証されている。二次損傷は、一次的事象の数分ないし数日後に発生するとすれば、この種の損傷を薬理学的に防止し、結果として生じる結果を有意に改善する好機が存在する。しかし、初めに、二次損傷を構成する因子を特定し、次いで、損傷過程を阻害する「抗因子」を開発しなければならない。
【０００４】
本発明者らの研究は、脳損傷後の二次損傷因子を特定し、介入する治療法を開発することに集中した。損傷後の結果を決定するのに決定的に重要であるとして、本発明者らが以前に特定した因子の一つは1-4、脳のマグネシウムイオン濃度であった。このイオンは、脳損傷後に活性化される、数多くの生化学的および生理学的過程の調節因子である。実際、マグネシウムイオン濃度の低下は、損傷過程を増悪させることが観察されたが、マグネシウムイオン濃度の上昇は、損傷過程を減衰させ、改善された結果を招くことが注目された5。それ以来、マグネシウムによる脳損傷の治療は、一次事象の２４時間後までに投与されたときでさえ、効果的であることが示されており1,6-10、実験動物の研究における治療の成功は、その後、ヒトの脳損傷における臨床試験へと導いた。
【０００５】
マグネシウム投与による脳損傷後の欠損の減衰にもかかわらず、治療後に持続する運動および認識欠損が依然として存在することが、明らかであった。本発明者らの注意は、特に、より若い動物では、脳内の水の蓄積（すなわち脳浮腫または脳腫脹）が依然として存在し、これが有意な危険因子を与え得ることに引き付けられた。実際、最近の臨床研究では11、遅延性脳腫脹は、脳損傷の若い犠牲者で記録されたすべての死の５０％の原因であった。
【０００６】
（発明の開示）
したがって、本発明の目的は、脳損傷に関連する処置の方法、およびこの方法に用いるための処方物を提供することである。
【０００７】
本発明の一態様における処方物は、サブスタンスＰ受容体拮抗物質およびマグネシウム化合物を含んでいて、マグネシウム化合物およびサブスタンスＰ受容体拮抗物質の併用は、損傷に対して、単独で用いたマグネシウム化合物またはサブスタンスＰ受容体拮抗物質のいずれより多大な防護を招く。
【０００８】
本発明の方法は、脳損傷に罹患している患者に該処方物を投与する段階を包含する。あるいは、上述のとおり、該処方物の成分を、それぞれ、別個にか、または治療法の効果に影響しない時間的遅延、たとえば１〜３０分か２４時間まで、によって分離する。
【０００９】
サブスタンスＰは、興奮性神経伝達物質であり、疼痛の伝達に役割を有し、構造ＲＰＫＰＥＥＦＦＧＬＭ−ＮＨ2を有するペプチドである。それは、視床下部、ＣＮＳおよび腸に由来し、Ｇ１路の平滑筋収縮を増大させる。
【００１０】
サブスタンスＰは、ＮＫ１受容体（すなわち、ニューロキニン１受容体）、ＮＫ２受容体およびＮＫ３受容体を包含する数多くの受容体と結合することが公知である。これらの受容体は、脳への血液の巡回に役割を有すると考えられる。
【００１１】
したがって、サブスタンスＰ拮抗物質は、上に参照された受容体のいずれか一つとのサブスタンスＰの結合を阻害する物質である。適するサブスタンスＰ拮抗物質のリストを、本明細書に添付の第１、２および３表に参照する。
【００１２】
本発明の方法の処方物に用いてよいサブスタンスＰ拮抗物質を構成するとして、米国特許第5,990,125号明細書（参照により本明細書に組み込まれる）に記載されたとおりのＮＫ１受容体拮抗物質も、参照され得る。これには、構造Ｉａ、Ｉｂ、Ｉｃ、Ｉｄ、Ｉｅ、Ｘ、XVI、XVII、XVIII、XIX、XXおよびXXIを有する化合物はもとより、米国特許第5,990,125号明細書の第３３欄に記載されたとおりの、キヌクリジン、ピペリジン、エチレンジアミン、ピロリジンおよびアザボルナン誘導体を含むその他の拮抗物質、ならびにサブスタンスＰ受容体拮抗物質としての活性を示す関連化合物が具体的に参照される。
【００１３】
そのような受容体拮抗物質は、米国特許第4,990,125号明細書の第３４欄に参照された投与量を考慮して、かつ米国特許第5,990,125号明細書の第３４欄に参照されたとおりの、様々な投与形態で、すなわち、単独でか、または製薬上許容され得る担体もしくは希釈剤とともに、経口投与または非経口投与によって用いてよい。
【００１４】
本発明に用いるためのサブスタンスＰ受容体拮抗物質としての、様々な物質の活性も、米国特許第5,990,125号明細書の第３５〜３６欄に参照されたアッセーによって決定してよい。
【００１５】
米国特許第5,977,104号明細書（これも、参照によって本明細書に全体的に組み込まれる）に記載されたサブスタンスＰ受容体拮抗物質も、この引用文献中に参照された、様々な投与形態および投与量を含めて参照され得る。
【００１６】
様々なペプチド拮抗物質を記載する米国特許第4,481,139号明細書も参照されてよく、これも、参照によって本明細書に全体的に組み込まれる。
【００１７】
本明細書に用いられる限りでの用語「サブスタンスＰ」は、米国特許第4,481,139号明細書（参照によって本明細書に全体的に組み込まれる）に記載されたとおりの、断端された様々な形態または類似体も、その対象範囲内に包含し得ることも理解されると思われる。
【００１８】
本発明に用いるためのサブスタンスＰ拮抗物質として用いるための、様々なピペリジンおよびモルホリン誘導体を参照する米国特許第4,985,896号明細書、または米国特許第5,981,520号明細書に記載されたとおりのピペラジノ誘導体も参照され得る。これらの引用文献は、それぞれ、参照によって本明細書に全体的に組み込まれる。
【００１９】
本明細書に用いるためのＮＫ１またはＮＫ２拮抗物質として、米国特許第5,998,444号明細書（これも、参照によって本明細書に全体的に組み込まれる）に参照されたピペリジニル化合物も、参照され得る。
【００２０】
米国特許第4,981,744号明細書に参照されたタキキニン拮抗物質も、サブスタンスＰ拮抗物質として本発明に用いてよいことも認識されると思われ、したがって、この引用文献も、本明細書に全体的に組み込まれる。
【００２１】
Ｎ−ベンジル−４−トリルニコチンアミドおよび関連化合物を、本発明に用いるためのＮＫ１受容体拮抗物質として参照するEP-A-1035115も参照されてよく、参照によって本明細書に全体的に組み込まれる。
【００２２】
様々なフェニルおよびピリジニル誘導体を、本明細書に用いるためのＮＫ１受容体拮抗物質として参照する、国際刊行物のWO 0050398（参照によって本明細書に全体的に組み込まれる）が参照され得る。
【００２３】
それぞれ、３−フェニルピリジン、ビフェニル誘導体、５−フェニルピリミジン誘導体および４−フェニルピリミジン誘導体を参照する、国際刊行物のWO 0050401、WO 0053572、WO 0073278およびWO 0073279も参照されてよく、これらの明細書も、参照によって本明細書に全体的に組み込まれる。これらの明細書は、本明細書に用いるためのＮＫ１受容体拮抗物質を参照している。
【００２４】
本明細書に用いるための、サブスタンスＰ拮抗物質として用い得る、サブスタンスＰ拮抗物質の修飾、またはサブスタンスＰフラグメントを記載する、1998 Sigma Catalogue、より詳しくはその1,194〜1,997ページも参照され得る。この刊行物も、参照によって本明細書に全体的に組み込まれる。
【００２５】
マグネシウム化合物に関しては、塩化マグネシウム、硫酸マグネシウム、シュウ酸マグネシウム、グルコン酸マグネシウム及びその他の無害なマグネシウム塩のような、適するいかなるマグネシウムイオン源を含んでもよい。
【００２６】
加えて、本発明による製剤調製品は、防腐剤、可溶化剤、安定剤、湿潤剤、乳化剤、甘味料、着色剤、香味料、浸透圧を変えるための塩、緩衝剤、遮蔽剤または抗酸化剤も含有することができる。それらは、治療上価値あるさらに別の物質も含有することができる。したがって、本明細書に用いられる用語「含む」は、この文脈中で解釈しなければならない。投与量は、広い限度内で変化することができ、当然、それぞれの特定の事例における個別的要件に合わせることができる。一般的には、患者あたり１〜２０，０００mg、好ましくは１０〜５，０００mg、より好ましくは５０〜２，０００mgのサブスタンスＰ受容体拮抗物質が適切なはずであると思われる。
【００２７】
本発明の概念の発生に関しては、本発明者らによって、損傷後の脳内の急性水蓄積の一つの理由は、血管原性浮腫形成の結果であることが確立された。これは、血液脳関門の透過性が増大し、そのため、血管性のタンパク質および水が脳内の細胞外空間に進入し、腫脹を生じるのを許すことによって生じる。この血液脳関門の透過性増大が、損傷後の神経学的欠損の発生にいかに寄与するかを検証した研究は、僅かであるにすぎず、脳腫脹の阻害が、結果を改善するか否かを調査した研究は、皆無である。偏頭痛の研究は12,13、脳硬膜（外側の髄膜層）の脈管系が、サブスタンスＰ放出の結果として、血管成分に対して、より透過性になることを示唆している。そのため、本発明者らは、サブスタンスＰは、脳の脈管系に対して同様の効果を有する可能性があって、そのような効果が、血液脳関門透過性の上昇、および血管原性脳浮腫へと導き得るとの仮説を立てた。さらに、本発明者らは、サブスタンスＰ受容体拮抗物質の投与は、損傷後の脳腫脹と、遅延性神経学的欠損の発生とを妨げ得るとの仮説を立てた。この仮説は、上記に参照した、水は、血管原性浮腫形成の結果として脳内に蓄積するとの本発明者らの発見の結果であった。
【００２８】
したがって、本発明のもう一つの態様では、脳障壁透過性および／または血管原性脳浮腫を低減するための、サブスタンスＰ受容体拮抗物質の用途が提供される。
【００２９】
（実験）
表１、２および３から明らかなとおり、現在、数多くの商業的に合成されたサブスタンスＰ受容体拮抗物質が、標準的な学術的化学品供給者から入手可能である。本発明者らは、自然に血液脳関門を横断できるその可能性を限定する、その低い脂溶性と、それが比較的廉価であることとに基づいて、化合物Ｎ−アセチル−Ｌ−トリプトファンを用いることを選んだ。脳損傷の３０分後に与えた、２４６mg/kg（生理食塩水の担体）という静脈内用量でのＮ−アセチル−Ｌ−トリプトファンの投与は、バーンズ環状迷路によって査定された限りで、損傷した動物の脳内での認識結果の有意な改善を招いた。同様に、オータロッド試験によって査定された限りで、動物の運動結果の有意な改善があった。結果のこれらの改善は、脳損傷の２４時間後に明白であり、１４日の査定期間にわたって持続した。対照（担体で試験した）動物は、試験されたすべての時点で、治療された動物より有意に劣る神経学的結果を有する。
【００３０】
Ｎ−アセチル−Ｌ−トリプトファンを投与された動物は、担体投与された対照と比較した限りで、損傷の２４時間後の脳の水蓄積（すなわち脳浮腫）の有意な減少があった。これは、Ｎ−アセチル−Ｌ−トリプトファンが、損傷の５時間後、すなわち脳損傷後の最高の血液脳関門透過性に関連する時間に、エヴァンスブルーの脳浸透を低下させたという観察と一致した。こうして、脳損傷の３０分後に投与されたＮ−アセチル−Ｌ−トリプトファンは、血液脳関門透過性を低下させ、血管原性浮腫形成を低下させた。これらの効果が、ＮＫ１拮抗物質の非透過性処方物によって注目されたことは、該効果が、主として、血管性受容体によって仲介され、中枢性受容体に依存しなかったことを示唆する。
【００３１】
２４．６mg/kgでのＮ−アセチル−Ｌ−トリプトファンの投与は、脳損傷動物の認識結果も有意に改善した。しかし、この薬物は、運動結果に対しては、より少ない有益な効果を有した。その上、投与されたすべての動物で、何らかの残留性の認識および運動欠損が常に注目されたため、ＮＫ１拮抗物質の投与の有益な効果は、重い性質の損傷ではなく、軽い重篤度の損傷が誘導されたときには、より不明確であった。これは、軽い頭部損傷が脳損傷患者において最高の発生率を有するとすれば、主要な限定である。
【００３２】
（マグネシウムおよびＮ−アセチル−Ｌ−トリプトファンの併用）
脳損傷の最も一般的な形態は、軽度の頭部損傷である。世界神経外科医連盟World Federation of Neurological Surgeonsが来年（2000年）導入しようとする指針は、嘔吐、悪心、意識喪失または健忘症のようないかなる併発症もともなう、軽度の頭部損傷のすべての症例を、病院に提示しなければならないことを勧告すると思われる。これは、保健系統に対して、これらの個人を、二次損傷がそれ以上発生しないよう、適切に治療するための顕著な圧力を加えると思われる。現在、そのような治療法は皆無である。
【００３３】
Ｎ−アセチル−Ｌ−トリプトファンによる本発明者らの結果は、この化合物が、頭部損傷後に血液脳関門を閉鎖し、脳腫脹または脳浮腫を低減することを示唆する。これは、遅延性脳腫脹を特に発症しやすい、頭部損傷の若い犠牲者には極めて重要である。さらに、マグネシウム療法による本発明者らの結果は、マグネシウム投与が、血液脳透過性の増大に必ずしも付随しない、神経学的欠損を軽減するのに効果的であることを示唆する。したがって、本発明者らは、サブスタンスＰ拮抗物質とマグネシウム化合物または塩との併用が、重篤度に関わりなく、脳損傷の治療のための特に効果的な処置法であることを提唱する。
【００３４】
２４６mg/kgのＮ−アセチル−Ｌ−トリプトファンと３０mg/kgの硫酸マグネシウムとの組合せ投与（静脈内）は、運動および認識双方の欠損の、単独でのいずれの薬物で得られたそれより有意に多大な、傑出した減衰を招いた（図１および図２）。
【００３５】
組合せ処方物中の化合物は、それぞれ、脳損傷に用いるのに特に魅力的にさせる、数多くの特性を有する。
【００３６】
サブスタンスＰ（ＳＰ）拮抗物質は、サブスタンスＰで誘導された不安を打ち消すことによって、気分を急速に改善することが示された。したがって、損傷後の抑うつを治療するのに効果的である。上記の研究から、ＳＰ拮抗物質は、血液脳関門透過性を低下させ、血管原性浮腫の形成、および損傷後の脳腫脹または脳浮腫を阻害することが明白である。該拮抗物質は、疼痛を抑えることも示された。海馬および線条体、すなわち、脳の、学習および記憶に関連することが公知である部分には、極めて多くのサブスタンスＰ受容体が存在する。このため、ＳＰ拮抗物質による結合の阻害は、学習および記憶におけるサブスタンスＰ誘導性欠損を防止し得る。上に提示された本発明者らの証拠は、これが該当し得ることを示唆する。これは、以前には決して示されたことがなかった。実際、脳損傷におけるサブスタンスＰ、またはいかなる神経ペプチドの役割に関する文献も、皆無であった。
【００３７】
マグネシウムは、３００を越える細胞性酵素に影響する。したがって、マグネシウムが、結果を改善し得る数多くの標的を有することは、驚くにあたらない。これらは、とりわけ、グルタミン酸で誘導される興奮性毒性の遮断、反応性酸素種の膜安定性の改善および産生低減、エネルギー状態の改善、カルシウムチャンネルの阻害、神経伝達物質の放出低減、ミトコンドリア移行孔の開口阻害、ならびにアポトーシスの阻害を包含する。注目すべきことに、それは、サブスタンスＰのグルタミン酸誘導性放出も阻害する。生理学的には、マグネシウムは、脳の血流を改善し、脳の血管痙攣を軽減し、血管性セラミドおよびプロスタグランジンの産生を低下させることが示されている14-17。
【００３８】
マグネシウムおよびサブスタンスＰ拮抗物質の併用は、神経損傷に対して、単独で用いたいずれの薬物より多大な防護を招く。
【００３９】
本発明者らは、以前に、マグネシウムが、１６〜６０mg/kgの範囲の静脈内用量で投与したとき、外傷に有益な効果を有することを示した。筋内注射として投与したときは、有効用量は、４５〜９０mg/kgで変動する。標的は、血中の遊離マグネシウム濃度を約１．０mMまで上昇させることであって、これは、正常な血中遊離マグネシウム濃度の二倍である。用いたマグネシウム塩に関わりなく、有益な結果が観察される。
【００４０】
サブスタンスＰ拮抗物質による本発明者らの研究は、効果的な静脈内用量は、２４．６〜２４０．６mg/kgまたはそれ以上で変動して、用量が多ければそれだけ、運動結果に対する有益な効果が多大であることを立証した。その上、これらの用量は、低い脂溶性を有し、そのため限定された血液脳関門透過性を有する拮抗物質に適合する。高度に脂溶性である処方物は、同じ有益な作用を強いるはずであると思われるが、不適切となり得る中枢介在性の副作用があり得る。
【００４１】
併用したとき、該処方物は、個別成分について記載された範囲で変動し得る。本発明者らは、個別成分について記載された最大静脈内用量を用いて、優れた結果を達成した。
【００４２】
マグネシウム／ＳＰ拮抗物質の併用は、下記の状態で役立つことが期待される：
【００４３】
・外傷性脳損傷後の「救急」予防処置として、
・脳振盪を包含する、軽い頭部損傷後の「救急」予防処置として、
・発作、低酸素症、および浮腫が関連するいかなる形態の脳損傷も包含する、非外傷性脳損傷後の治療法として、
・脳損傷後の維持療法として。
【００４４】
【表１】
【表２】
【表３】
【図面の簡単な説明】
【図１】 損傷後の時間（日）とロータロッド評点の関係を示す図である。
【図２】 損傷後の時間（日）とバーンズ迷路評点の関係を示す図である。[0001]
(Field of Invention)
The present invention relates to a method for the treatment of brain, spinal cord and nerve injury. Formulations that are particularly useful for the method are also provided.
[0002]
Damage to the brain leads to the development of motor and cognitive deficits, which contribute to the significant morbidity experienced by survivors of brain injury. In addition, it has the highest incidence among young members of society. Thus, damage to the brain causes the greatest loss of productive life compared to any other disease process. Nevertheless, there is no effective treatment to improve the outcome after brain injury. We disclose the use of the therapy as a powerful pharmacological intervention for the treatment of brain injury. Using this therapy has been found to significantly improve both motor and cognitive outcomes in mild to severe experimental brain injury and to have beneficial effects in the treatment of spinal cord and nerve injury. It was.
[0003]
(Background of the Invention)
It is well known that brain damage leads to the development of neurological deficits through two mechanisms. The first of these is known as the primary mechanism. These occur at the time of the injury event and include mechanical processes such as nerve fiber rupture, laceration, stretching and compression. Little can be done to this type of damage once it has occurred. The second mechanism is secondary injury, which involves biochemical and physiological processes initiated by primary injury, but appears with time after injury. Many morbidities after brain injury have been demonstrated to be associated with the occurrence of this secondary injury. If secondary damage occurs minutes or days after the primary event, there is an opportunity to pharmacologically prevent this type of damage and significantly improve the resulting outcome. But first, the factors that make up the secondary damage must be identified, and then “anti-factors” that inhibit the damage process must be developed.
[0004]
Our work has focused on identifying secondary intervention factors after brain injury and developing treatments to intervene. One of the factors we previously identified as critical to determining post-injury results was 1-4 , brain magnesium ion concentration. This ion is a regulator of many biochemical and physiological processes that are activated after brain injury. Indeed, 5 decrease in the magnesium ion concentration is that exacerbate damage process was observed, increased magnesium ion concentration, which attenuates the injury process, may lead to improved results were noted. Since then, treatment of brain damage with magnesium has been shown to be effective even when administered up to 24 hours after the primary event 1,6-10 , with successful treatment in experimental animal studies Subsequently led to clinical trials in human brain injury.
[0005]
Despite attenuation of defects after brain injury with magnesium administration, it was clear that there were still motor and cognitive deficits that persisted after treatment. Our attention was drawn to the fact that water accumulation in the brain (ie brain edema or brain swelling) was still present, particularly in younger animals, which could give significant risk factors. In fact, in a recent clinical study 11 , delayed brain swelling was responsible for 50% of all deaths recorded in young victims of brain injury.
[0006]
(Disclosure of the Invention)
Accordingly, it is an object of the present invention to provide a method of treatment associated with brain injury and a formulation for use in this method.
[0007]
The formulation in one embodiment of the present invention comprises a substance P receptor antagonist and a magnesium compound, wherein the combination of the magnesium compound and the substance P receptor antagonist is a magnesium compound or substance used alone for injury. It leads to greater protection than any of the P receptor antagonists.
[0008]
The method of the invention includes administering the formulation to a patient suffering from brain injury. Alternatively, as described above, the components of the formulation are each separated separately or by a time delay that does not affect the effectiveness of the therapy, eg, 1-30 minutes or up to 24 hours.
[0009]
Substance P is an excitatory neurotransmitter, has a role in the transmission of pain, a peptide having the structure RPKPEEFFGLM-NH 2. It is derived from the hypothalamus, CNS and intestine and increases G1 tract smooth muscle contraction.
[0010]
Substance P is known to bind to a number of receptors including NK1 receptor (ie,
[0011]
Accordingly, a substance P antagonist is a substance that inhibits the binding of substance P to any one of the receptors referenced above. A list of suitable substance P antagonists is referenced in Tables 1, 2 and 3 attached hereto.
[0012]
An NK1 receptor antagonist as described in US Pat. No. 5,990,125 (incorporated herein by reference) as constituting a substance P antagonist that may be used in the formulation of the method of the present invention, Reference may be made. This includes compounds having the structures Ia, Ib, Ic, Id, Ie, X, XVI, XVII, XVIII, XIX, XX and XXI, as described in column 33 of US Pat. No. 5,990,125. Reference is specifically made to other antagonists, including quinuclidine, piperidine, ethylenediamine, pyrrolidine and azabornane derivatives, and related compounds exhibiting activity as substance P receptor antagonists.
[0013]
Such receptor antagonists are considered in consideration of the dosage referred to in column 34 of US Pat. No. 4,990,125 and as referenced in column 34 of US Pat. No. 5,990,125, It may be used in various dosage forms, ie, alone or with a pharmaceutically acceptable carrier or diluent by oral or parenteral administration.
[0014]
The activity of various substances as substance P receptor antagonists for use in the present invention may also be determined by the assay referred to in columns 35-36 of US Pat. No. 5,990,125.
[0015]
The substance P receptor antagonists described in US Pat. No. 5,977,104, which is also incorporated herein by reference in its entirety, are also described in various dosage forms and administrations referenced in this reference. Reference can be made including quantities.
[0016]
Reference may also be made to US Pat. No. 4,481,139, which describes various peptide antagonists, which are also hereby incorporated in their entirety by reference.
[0017]
As used herein, the term “substance P” refers to various truncated forms as described in US Pat. No. 4,481,139 (incorporated herein by reference in its entirety). It will also be understood that analogs may be included within the scope.
[0018]
See also US Pat. No. 4,985,896 or piperazino derivatives as described in US Pat. No. 5,981,520 which refers to various piperidine and morpholine derivatives for use as substance P antagonists for use in the present invention. Can be done. Each of these citations is incorporated herein by reference in its entirety.
[0019]
Reference may also be made to piperidinyl compounds referred to in US Pat. No. 5,998,444 (also incorporated herein by reference in its entirety) as NK1 or NK2 antagonists for use herein.
[0020]
It will be appreciated that tachykinin antagonists referenced in US Pat. No. 4,981,744 may also be used in the present invention as substance P antagonists, and thus this reference is also incorporated herein in its entirety. Incorporated.
[0021]
Reference may also be made to EP-A-1035115, which references N-benzyl-4-tolylnicotinamide and related compounds as NK1 receptor antagonists for use in the present invention, which is hereby incorporated by reference in its entirety. .
[0022]
Reference may be made to the international publication WO 0050398 (incorporated herein by reference in its entirety), which refers to various phenyl and pyridinyl derivatives as NK1 receptor antagonists for use herein.
[0023]
Reference may also be made to the international publications WO 0050401, WO 0053572, WO 0073278 and WO 0073279, which refer to 3-phenylpyridine, biphenyl derivatives, 5-phenylpyrimidine derivatives and 4-phenylpyrimidine derivatives, respectively. Is also incorporated herein by reference in its entirety. These specifications refer to NK1 receptor antagonists for use herein.
[0024]
Reference may also be made to the 1998 Sigma Catalog, more particularly pages 1,194 to 1,997, which describe substance P antagonist modifications, or substance P fragments, which can be used as substance P antagonists for use herein. This publication is also incorporated herein by reference in its entirety.
[0025]
With respect to magnesium compounds, any suitable source of magnesium ions may be included such as magnesium chloride, magnesium sulfate, magnesium oxalate, magnesium gluconate and other harmless magnesium salts.
[0026]
In addition, the preparations according to the invention can be used as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts for altering osmotic pressure, buffering agents, screening agents or Oxidizing agents can also be included. They can also contain still other substances of therapeutic value. Accordingly, the term “comprising” as used herein must be interpreted in this context. The dosage can vary within wide limits and of course can be tailored to the individual requirements in each particular case. In general, it appears that 1 to 20,000 mg, preferably 10 to 5,000 mg, more preferably 50 to 2,000 mg of substance P receptor antagonist per patient should be appropriate.
[0027]
With regard to the development of the inventive concept, the inventors have established that one reason for acute water accumulation in the brain after injury is the result of angiogenic edema formation. This occurs by increasing the permeability of the blood brain barrier and thus allowing vascular proteins and water to enter the extracellular space in the brain and cause swelling. Only a few studies have examined how this increased blood-brain barrier permeability contributes to the development of post-injury neurological deficits, and whether inhibition of brain swelling improves outcomes? There are no studies that investigated this. Migraine studies 12,13 suggest that the cerebral dura (outer meningeal layer) vasculature becomes more permeable to vascular components as a result of substance P release. Therefore, the present inventors have found that substance P may have a similar effect on the cerebral vasculature, and such an effect results in increased blood brain barrier permeability and vasogenic brain. He hypothesized that it could lead to edema. In addition, the inventors hypothesized that administration of substance P receptor antagonists could prevent post-injury brain swelling and the development of delayed neurological deficits. This hypothesis was the result of our discovery that water, referred to above, accumulates in the brain as a result of angiogenic edema formation.
[0028]
Accordingly, in another aspect of the present invention there is provided the use of substance P receptor antagonists to reduce brain barrier permeability and / or vasogenic brain edema.
[0029]
(Experiment)
As is apparent from Tables 1, 2 and 3, a number of commercially synthesized substance P receptor antagonists are currently available from standard academic chemical suppliers. We use the compound N-acetyl-L-tryptophan on the basis of its low fat solubility and its relatively low cost, which limits its ability to cross the blood brain barrier naturally. I chose that. Administration of N-acetyl-L-tryptophan at an intravenous dose of 246 mg / kg (saline carrier) given 30 minutes after brain injury was only allowed to occur in the injured animals as assessed by the Burns Ring Maze. This resulted in a significant improvement in the recognition results in the brain. Similarly, there was a significant improvement in animal exercise results as assessed by the autorod test. These improvements in results were evident 24 hours after brain injury and persisted over the 14 day assessment period. Control (tested with carrier) animals have neurological results that are significantly inferior to treated animals at all time points tested.
[0030]
Animals receiving N-acetyl-L-tryptophan had a significant reduction in brain water accumulation (ie cerebral edema) 24 hours after injury as compared to vehicle-treated controls. This is consistent with the observation that N-acetyl-L-tryptophan reduced Evans Blue's
[0031]
Administration of N-acetyl-L-tryptophan at 24.6 mg / kg also significantly improved the recognition results of brain-injured animals. However, this drug had less beneficial effects on exercise results. In addition, since any residual recognition and motor deficits have always been noted in all animals administered, the beneficial effects of NK1 antagonist administration are not severe nature damage, but minor severity damage. When guided, it was more unclear. This is a major limitation if mild head injury has the highest incidence in brain-injured patients.
[0032]
(Combination of magnesium and N-acetyl-L-tryptophan)
The most common form of brain injury is mild head injury. The World Federation of Neurological Surgeons that the World Federation of Neurological Surgeons will introduce next year (2000) is a guideline for all cases of mild head injury with any complications such as vomiting, nausea, loss of consciousness or amnesia. It seems to recommend that it must be presented to the hospital. This appears to put significant pressure on the health system to properly treat these individuals so that no further secondary damage occurs. Currently there is no such treatment.
[0033]
Our results with N-acetyl-L-tryptophan suggest that this compound closes the blood brain barrier after head injury and reduces brain swelling or edema. This is extremely important for young victims of head injury who are particularly prone to developing delayed brain swelling. Furthermore, our results with magnesium therapy suggest that magnesium administration is effective in reducing neurological deficits that are not necessarily associated with increased blood brain permeability. The inventors therefore propose that the combination of substance P antagonists and magnesium compounds or salts is a particularly effective treatment for the treatment of brain injury, regardless of severity.
[0034]
The combined administration of 246 mg / kg N-acetyl-L-tryptophan and 30 mg / kg magnesium sulfate (intravenous) was significantly more than that obtained with either drug alone, in both motor and cognitive deficits. It resulted in a great deal of outstanding attenuation (FIGS. 1 and 2).
[0035]
Each compound in the combination formulation has a number of properties that make it particularly attractive for use in brain injury.
[0036]
Substance P (SP) antagonists have been shown to rapidly improve mood by countering anxiety induced by substance P. It is therefore effective in treating post-injury depression. From the above studies, it is clear that SP antagonists reduce blood brain barrier permeability, inhibit vasogenic edema formation, and post-injury brain swelling or edema. The antagonist has also been shown to suppress pain. There are a large number of substance P receptors in the hippocampus and striatum, the part of the brain known to be associated with learning and memory. Thus, inhibition of binding by SP antagonists can prevent substance P-induced deficits in learning and memory. Our evidence presented above suggests that this may be the case. This has never been shown before. In fact, there was no literature on the role of substance P or any neuropeptide in brain injury.
[0037]
Magnesium affects over 300 cellular enzymes. It is therefore not surprising that magnesium has numerous targets that can improve the results. These include, among other things, blocking excitotoxicity induced by glutamate, improving membrane stability and production of reactive oxygen species, improving energy status, inhibiting calcium channels, reducing neurotransmitter release, mitochondria transition pores Inhibiting the opening of as well as inhibiting apoptosis. Of note, it also inhibits glutamate-induced release of substance P. Physiologically, magnesium has been shown to improve cerebral blood flow, reduce cerebral vasospasm, and reduce vascular ceramide and prostaglandin production 14-17 .
[0038]
The combination of magnesium and substance P antagonist results in greater protection against nerve damage than any drug used alone.
[0039]
We have previously shown that magnesium has a beneficial effect on trauma when administered at intravenous doses in the range of 16-60 mg / kg. When administered as an intramuscular injection, the effective dose varies from 45 to 90 mg / kg. The target is to increase the blood free magnesium concentration to about 1.0 mM, which is twice the normal blood free magnesium concentration. Regardless of the magnesium salt used, beneficial results are observed.
[0040]
Our studies with substance P antagonists have shown that effective intravenous doses vary from 24.6 to 240.6 mg / kg or more, the higher the dose, the more beneficial effects on exercise outcome Proved to be great. Moreover, these doses are compatible with antagonists that have low fat solubility and thus limited blood brain barrier permeability. A formulation that is highly fat-soluble will likely impose the same beneficial effects, but there may be centrally mediated side effects that may be inappropriate.
[0041]
When used in combination, the formulation may vary within the ranges stated for the individual components. We have achieved excellent results using the maximum intravenous dose described for the individual components.
[0042]
The magnesium / SP antagonist combination is expected to be useful in the following conditions:
[0043]
・ As an "emergency" preventive measure after traumatic brain injury
・ As `` emergency '' prevention treatment after minor head injury, including brain shaking,
As a treatment after atraumatic brain injury, including any form of brain injury associated with stroke, hypoxia, and edema,
・ As maintenance therapy after brain injury.
[0044]
[Table 1]
[Table 2]
[Table 3]
[Brief description of the drawings]
FIG. 1 is a diagram showing the relationship between time (days) after damage and rotarod score.
FIG. 2 is a diagram showing the relationship between time (days) after injury and Barnes maze score.
Claims (20)
前記サブスタンスＰ受容体拮抗物質が、Ｎ−アセチル−Ｌ−トリプトファンである注射用処方物。An injectable formulation for the treatment of brain, spinal cord and nerve injury comprising a substance P receptor antagonist in combination with a magnesium compound comprising :
An injectable formulation, wherein the substance P receptor antagonist is N-acetyl-L-tryptophan .
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| PCT/AU2001/000046 WO2001052844A1 (en) | 2000-01-18 | 2001-01-18 | Brain, spinal and nerve injury treatment |
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